Blending problem-based learning and peer-led team learning, in an open ended ‘home-grown’pharmaceutical chemistry case study

Pharmaceutical chemistry, medicinal chemistry and the drug discovery process require experienced practitioners to employ reasoned speculation in generating creative ideas, which can be used to evolve promising molecules into drugs. The ever-evolving world of pharmaceutical chemistry requires university curricula that prepare graduates for their role as designers with the capability of applying complex concepts in pharmaceutical chemistry, thereby improving the decision-making process. Common methods of teaching drug discovery, including the linear nature of the traditional case study model, do not provide a realistic picture of the underlying complexity of the process, nor do they equip students with the appropriate tools for personal sense making and abstraction. In this work, we discuss the creation of an open-ended, nonlinear case study for 3rd year pharmaceutical chemistry students, developed from drug discovery research conducted at Rhodes University. Furthermore, we discuss blending problem based learning (PBL) with peer-led team learning (PLTL) in the context of curriculum transformation, underpinned by the theory of semantic waves, to assist students in the early attainment of abstract concepts and answer questions of contextualisation, personal sense making, relatability, relevance and ultimately the skills for lifelong learning

Detection of the in vitro modulation of Plasmodium falciparum Arf1 by Sec7 and ArfGAP domains using a colorimetric plate-based assay:

The regulation of human Arf1 GTPase activity by ArfGEFs that stimulate GDP/GTP exchange and ArfGAPs that mediate GTP hydrolysis has attracted attention for the discovery of Arf1 inhibitors as potential anti-cancer agents. The malaria parasite Plasmodium falciparum encodes a Sec7 domain-containing protein - presumably an ArfGEF - and two putative ArfGAPs, as well as an Arf1 homologue (PfArf1) that is essential for blood-stage parasite viability. However, ArfGEF and ArfGAP-mediated activation/deactivation of PfArf1 has not been demonstrated

Synthesis, structure and in vitro anti-trypanosomal activity of non-toxic Arylpyrrole-Based Chalcone derivatives:

With an intention of identifying chalcone derivatives exhibiting anti-protozoal activity, a cohort of relatively unexplored arylpyrrole-based chalcone derivatives were synthesized in moderate to good yields. The resultant compounds were evaluated in vitro for their potential activity against a cultured Trypanosoma brucei brucei 427 strain. Several compounds displayed mostly modest in vitro anti-trypanosomal activity with compounds 10e and 10h emerging as active candidates with IC50 values of 4.09 and 5.11 µM, respectively. More importantly, a concomitant assessment of their activity against a human cervix adenocarcinoma (HeLa) cell line revealed that these compounds are non-toxic

Anti-seizure activity of African medicinal plants: The identification of bioactive alkaloids from the stem bark of Rauvolfia caffra using an in vivo zebrafish model

Epilepsy is one of the major chronic diseases that does not have a cure to date. Adverse drug reactions have been reported from the use of available anti-epileptic drugs (AEDs) which are also effective in only two-thirds of the patients. Accordingly, the identification of scaffolds with promising anti-seizure activity remains an important first step towards the development of new anti-epileptic therapies, with improved efficacy and reduced adverse effects. Herbal medicines are widely used in developing countries, including in the treatment of epilepsy but with little scientific evidence to validate this use. In the search for new epilepsy treatment options, the zebrafish has emerged as a chemoconvulsant-based model for epilepsy, mainly because of the many advantages that zebrafish larvae offer making them highly suitable for high-throughput drug screening

Recent Advances in Drug Discovery from South African Marine Invertebrates

Recent developments in marine drug discovery from three South African marine invertebrates, the tube worm Cephalodiscus gilchristi, the ascidian Lissoclinum sp. and the sponge Topsentia pachastrelloides, are presented. Recent reports of the bioactivity and synthesis of the anti-cancer secondary metabolites cephalostatin and mandelalides (from C. gilchristi and Lissoclinum sp., respectively) and various analogues are presented. The threat of drug-resistant pathogens, e.g., methicillin-resistant Staphylococcus aureus (MRSA), is assuming greater global significance, and medicinal chemistry strategies to exploit the potent MRSA PK inhibition, first revealed by two marine secondary metabolites, cis-3,4-dihydrohamacanthin B and bromodeoxytopsentin from T. pachastrelloides, are compared

Unexpected transformations of 3-(bromoacetyl)coumarin provides new evidence for the mechanism of thiol mediated dehalogenation of α-halocarbonyls

publisher versionThe mechanism for the thiol mediated dehalogenation of α-halogenated carbonyls has remained an unresolved problem, despite its ongoing application in synthetic organic chemistry. Nakamura and co-workers first proposed that net dehalogenation occurs via sequential nucleophilic substitutions, while Israel and co-workers concluded that the rate at which dehalogenation occurred suggested that dehalogenation proceeds in a single concerted step. In this study, we investigated the debromination and nucleophilic substitution of 3-(bromoacetyl)coumarin with a variety of thiophenols, whose electron donating or withdrawing natures resulted in large variations in the degree of nucleophilic substitution and dehalogenation products, respectively. Results from these experiments, in addition to an unexpected formation of thioether containing dibenzo[b,d]pyran-6-ones from a Robinson annulation, has provided new evidence for this disputed mechanism

Indolyl-3-ethanone-α-thioethers: a promising new class of non-toxic antimalarial agents

publisher versionThe success of chemotherapeutics in easing the burden of malaria is under continuous threat from ever-evolving parasite resistance, including resistance to artemisinin combination therapies. Therefore, the discovery of new classes of antimalarials which inhibit new biological targets is imperative to controlling malaria. Accordingly, we report here the discovery of indolyl-3-ethanone-α-thioethers, a new class of antimalarial compounds with encouraging activity. Synthesis of a focused library of compounds revealed important insight into the SAR of this class of compounds, including critical information regarding the position and chemical nature of substituents on both the thiophenol and indole rings. This investigation ultimately led to the discovery of two hit compounds (16 and 27) which exhibited nano molar in vitro antimalarial activity coupled to no observable toxicity against a HeLa cell line

Facile synthesis and biological evaluation of assorted indolyl-3-amides and esters from a single, stable carbonyl nitrile intermediate

publisher versionThe synthesis of biologically relevant amides and esters is routinely conducted under complex reaction conditions or requires the use of additional catalysts in order to generate sensitive electrophilic species for attack by a nucleophile. Here we present the synthesis of different indolic esters and amides from indolyl-3-carbonyl nitrile, without the requirement of anhydrous reaction conditions or catalysts. Additionally, we screened these compounds for potential in vitro antimalarial and anticancer activity, revealing 1H-indolyl-3-carboxylic acid 3-(indolyl-3-carboxamide)aminobenzyl ester to have moderate activity against both lines